Device and method for perfusing peritoneal dialyzing fluid

ABSTRACT

An instrument and method for continuous recirculation of peritoneal dialysate to infuse and drain out the dialysate automatically through catheters implanted in a peritoneal cavity of a human body. The recirculation instrument permits the reuse of protein which is permeated out from a patient&#39;s body, as an osmotic agent in peritoneal dialysate, in order to maintain a disinfected recirculating line, and to improve an ultrafiltration rate and clearance of uremic toxin. The recirculation method includes continuously draining the dialysate out of the peritoneal cavity, recirculating the dialysate through a closed line, filtering out a portion of the dialysate through a semipermeable membrane on the way, supplementing a comparable volume of fresh dialysate through a semipermeable membrane having a maximum permeable molecule of up to 5,000 dalton, and returning the dialysate into the peritoneal cavity.

[0001] This application is a divisional application of U.S. Ser. No.09/806,686, filed Apr. 4, 2001, which is a national phase application ofPCT/JP99/05535, filed Oct. 7, 1999

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to a peritoneal dialysis instrumentfor improving dialysis efficacy in removing excess liquid and uremictoxin by maintaining polymer osmotic agents in place of glucose in arecirculation line without requiring outside contact for the therapy ofchronicle renal failure disease.

[0004] 2. Description of the Related Art

[0005] Peritoneal dialysis has been applied as an effective therapy forrenal failure patients. The dialysis is performed so that dialysate isinfused into the peritoneal cavity from the dialysate bag through acatheter, which is implanted in the patient's peritoneal cavity, and thedialysate is stored in the cavity for a certain time. Then, thedialysate is drained out through the same catheter. This procedure isrepeated a few times a day.

[0006] This dialysis has a few advantages over hemodialysis from aphysiological point of view, as it purifies blood continuously throughthe patient's peritoneum, while hemodialysis uses artificial membranes.Also, peritoneal dialysis enables the patients to participate in socialactivity, and as a result, the dialysis has been widely applied.

[0007] In hemodialysis, ultrafiltration is achieved by raising thepressure of the blood line over that of the dialysate line. However, thesame method can not be applied to peritoneal dialysis. As a result, anosmotic agent is added into the dialysate so as to raise the osmoticpressure of the dialysate over that of plasma, and the dialysate isinfused into the peritoneal cavity so as to contact it to the peritoneumfor removing excess liquid from the patient's body. For this purpose,glucose has been used as an osmotic agent. However, adverse effects suchas the disfunctioning of the peritoneum due to the absorption of such alarge quantity of the osmotic agent into the patient body are nowrecognized as a serious problem.

[0008] For solving the aforementioned problem, the inventor of thepresent invention has proposed an instrument and a method by which serumprotein, such as albumin, globulin and the like which are permeated outthrough peritoneum into the dialysate, is recovered and refined, and isthen concentrated and reused with dialysate as the most physiologicalsubstitutes of glucose.

[0009] In these proposed processes, the following were disclosed:

[0010] (A) A method to dissolve the recovered and refined protein indialysate after which low molecular weight uremic toxin substances nothigher than 30,000 daltons are removed by the repeatedconcentration/dilution procedures with a semipermeable membrane, and toreuse it as a substitute of glucose. (Japanese Laid Open PatentApplication Hei 9-327511)

[0011] (B) A method to keep the abovementioned device and the componentsdisinfected. (Japanese Laid Open Patent Application Hei 10-85324)

[0012] (C) A method to separate the malignant solute in the solvent andrefine the protein by acidifying the protein and then de-acidifying itthrough water dialysis so as to deposit it at iso-electric pH (JapaneseLaid Open Patent Application Hei 9-302388)

[0013] Also, for carrying out the invention (C), it was disclosed thatthe device comprises the followings:

[0014] (D) An inflow line having a filter whose maximum pore size is100-300 nanometers for preventing bacteria invasion into the peritonealcavity; and

[0015] (E) A two step prefilter having a pore size between 5 and 200microns to remove blood cells, peritoneum mesothelial cells, fibrin andthe like suspended in the effluent when it is drained out fromperitoneal cavity.

[0016] A few attempts have been reported to utilize serum protein inascites (Hwang, E. R., Richard, D. O. Sherman, A. et al., DialyticAscites Ultra-filtration in Refractory Ascites, Am. J. Gastroenteral,77(9) :652-654, 1982, for example)

[0017] However, they did not refer to removing uremic toxin, becausetheir target was not a renal failure patient.

[0018] Also, a method to add a peritoneum protecting component of amolecular weight of not higher than 3,000 daltons recovered fromperitoneal dialysis effluent into dialysate (Japanese Laid Open PatentApplication Hei 8-337590). However the recovery and reuse of thecomponent of the molecular weight higher than 3,000 daltons is notsuggested.

[0019] When plasma protein that is permeated out of the patient body isreused as an osmotic agent in place of glucose, the following conditionsneed to be satisfied:

[0020] (I) To minimize the contact with atmosphere and foreign mattersso as to not denature the protein;

[0021] (II) To minimize plugging the semi-permeable membrane on therecirculation line, and to decrease the frequency of exchange; and

[0022] (III) To completely prevent the invasion of pathogenic bacteriaand endotoxin.

[0023] For the solution of the aforementioned (I) problem, it may besuggested that a filter is set at the exit of the catheter, or, as afurther perfect protection, a hollow fiber type semi-permeable membraneis set in a peritoneal cavity in order to keep the polymer in theperitoneal cavity. However, in those cases, complicated preventive meansare required to avoid plugging of the membrane, and the exchange of thefilter requires skillful care.

SUMMARY OF THE INVENTION

[0024] The present invention has developed a practical method and aninstrument for solving the aforementioned problems, by the combinationof either one of the following technologies:

[0025] [I] The drained dialysate is warmed up to a preset temperature,and then it is filtered through a prefilter for removing foreignmaterials so as to prevent the plugging of the filter.

[0026] [II] A semi-permeable membrane (having a cut-off point of up to30,000 dalton) filter is used for removing uremic toxin of low molecularweight and of middle molecular weight.

[0027] [III] A supplemental electrolyte solution is supplied through asemi-permeable membrane filter (having a cut-off point of up to 5,000dalton) for preventing the infection and invasion of endotoxin.

[0028] Also, the present inventor has found that by the use of thedevice, dialysate may be drained out of the peritoneal cavity and may berecirculated in a closed line. In addition, a portion of the dialysatemay be filtered out through a semi-permeable membrane to removemalignant component, and then, a fresh dialysate may be supplementedthrough a semipermeable membrane and returned automatically into theperitoneal cavity.

[0029] Briefly, the present invention relates to an instrument thatcomprises (a) a prefilter, (b) a first filter that comprises asemi-permeable membrane having a maximum permeable molecule of up to30,000 dalton, (c) a pump to lower the outside pressure of the firstfilter (b) relative to the inside pressure, (d) a second filter thatcomprises a semi-permeable membrane having a maximum permeable moleculeof 5,000 dalton, (e) and a pump to raise the pressure of a supplementalliquor line relative to the inside line of the second filter.

[0030] Also, the present invention relates to a method characterized inthat dialysate is drained out of the peritoneal cavity and recirculatedin a closed line, and a portion of the dialysate is filtered out througha semi-permeable membrane. Then, an equivalent volume of fresh dialysateis supplemented through a semi-permeable membrane having a maximumpermeable molecule of 5,000 dalton and is then returned into theperitoneal cavity.

[0031] As a favorable embodiment for carrying out the present invention,the following technologies may be adapted:

[0032] (1) A bacteria-free filter (having a maximum pore size of 100-300nanometers) is set up on the peritoneal cavity side of the inflow line'sjoint.

[0033] (2) Dialysate in the peritoneal cavity is recirculated through aperfectly closed and continuously connected and previously disinfectedline for keeping the protein not denatured in the automatic dialysaterecirculation instrument.

[0034] (3) A reverse flow prevention valve (anti-reverse flow valve) isset up on the withdrawn line.

[0035] (4) A closed chamber, of which the inside can not directly becontacted by fingers, is set up for disconnection and connectionprocedure by remote operation from outside, after the infusion ofdialysate for the daytime cycle before getting up in the morning.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036]FIG. 1 illustrates a Peritoneal Dialysate Recirculation Circuit ina nighttime state where the peritoneal dialysate recirculationinstrument is connected with the patient's outflow and inflow catheters,respectively, and the dialysate is recirculated.

[0037]FIG. 1(a) is an enlargement of the structure of the primary filterand the secondary filter of FIG. 1 and illustrates the flow of thedialysate and a supplemental solution therethrough.

[0038]FIG. 2 illustrates an exchanging method of an outflow line jointand an inflow line joint for:

[0039] (a) a disconnecting operation of the joint, which has beendirectly connected in the daytime (FIG. 3), and a rotation operation ofthe parts; and

[0040] (b) a rotating operation of the disconnected part so as to facethe part of peritoneal cavity side and the part of recirculationinstrument side, and a connecting operation of the parts so as to makeready for nighttime recirculation (FIG. 1).

[0041]FIG. 3 illustrates an O-shaped circuit of the catheter at anextracorporeal side (during a daytime state when the patient leaves andis away from the recirculation instrument for daily life) and hollowfibers in the peritoneal cavity.

EXPLANATION OF THE REFERENCE NUMERALS

[0042]1. Peritoneal Cavity

[0043]2. Outflow Catheter

[0044]3. Joint

[0045]4. Anti-Reverse Flow Valve

[0046]5. Outflow Line Joint

[0047]5 a. Patient Peritoneal Cavity Side Terminal of Outflow Line Joint

[0048]5 b. Recirculation Instrument Side Terminal of Outflow Line Joint

[0049]6. Heater

[0050]7. Prefilter

[0051]8. Bacteria-free Filter

[0052]9. Pump

[0053]10. Primary Filter

[0054]11. Secondary Filter

[0055]12. Suction Pump

[0056]13. Feeding Pump

[0057]14. Supplemental Solution Vessel

[0058]15. Pump

[0059]16. Pump

[0060]17 a. Container

[0061]17 b. Reservoir of Osmotic Agents

[0062]18. Warmer

[0063]19. Inflow Line Joint

[0064]19 a. Patient Peritoneal Cavity Side Terminal of Inflow Line Joint

[0065]19 b. Recirculation Instrument Side Terminal of Inflow Line Joint

[0066]20. Bacteria-free Filter

[0067]21. Joint

[0068]22. Inflow Catheter

[0069]23. Reverse Osmosis Membrane Water

[0070]24. Inlet Valve of Chemicals

[0071]25. Loupe-shape Hollow Fibers

[0072]26. Isolated Case

DETAILED DESCRIPTION OF THE INVENTION

[0073] The present invention will be explained with reference to FIG. 1.

[0074]FIG. 1 illustrates an outflow catheter 2 and an inflow catheter 22in a peritoneal cavity 1.

[0075] It happens to be observed often that when liquor is recirculatedfrom an inflow entrance to an outflow exit at a consistent rate, alocalized flow, a so-called channeling, is formed in the peritonealcavity; then, a portion of the liquor tends to stay at “dead spaces”.For solving this problem, a certain number of loop-shaped porous hollowfibers 25 are fixed at the end of the inflow catheter so that thedialysate may flow throughout the cavity as illustrated in FIG. 3.Instead of an outflow catheter 2, an outer lumen of a concentric doublelumen catheter may alternatively be used.

[0076] Outflow catheter 2 comprises joint 3, anti-reverse flow valve 4,and outflow joint 5, and the flow catheter is connected with heater 6and prefilter 7 in series.

[0077] Outflow joint 5 comprises peritoneal side part 5 a and instrumentside part 5 b, as illustrated in FIG. 3. During recirculation time,which occurs at night, the parts 5 a and 5 b are connected together. Thejoint 5 has the structure of male/female parts, which are directlyadaptable to each counterpart of inflow joint 19, as is discussedfurther below. During the daytime, which is when dialysate is notrecirculated but is stored in the peritoneal cavity, the joint part 5 ais connected with the joint part 19a, and the joint part 5 b isconnected with the joint part 19 b, thereby forming the circuitillustrated in FIG. 3.

[0078] The dialysis effluent that is drained out of the patient'speritoneal cavity contains peritoneum mesothelium cells, leucocytecells, deposited fibrin, and the like. These foreign particles may beseparated from the filtrate with prefilter 7.

[0079] Fibrinogen in the dialysate effluent tends to be deposited out asfibrin after prefiltration, and it plugs the filter. This has often beenexperienced when plasma and humor is filtered. For preventing theplugging problems, it is desirable to warm up the effluent up to 55-60°C. by means of a heater before prefiltration.

[0080] After the dialysate is passed through a bacteria-free filter 8,it is flown by pump 9 to the first filter 10 and then to the secondfilter 11. The first filter has a semi-permeable membrane of a maximumpermeable molecule of up to 30,000 dalton, greater than that of2-microglobulin, for example. By filtering out a portion of thedialysate through this filter, middle molecule malignant components,such as a 2-microglobulin of the molecular weight of 11,800 daltons, maybe removed.

[0081] After filtering through the first filter, the partially filtereddialysate is supplemented with a supplemental electrolyte solution. Thesupplemental solution is added through the second filter whosesemipermeable membrane does not pass endotoxin. The second filter has asemipermeable membrane of a maximum permeable molecule of up to 5,000dalton so that it can prevent invasion of bacteria and endotoxin.

[0082] Endotoxins are lipopolysaccharides, of which the largest oneshave a molecular weight of a few hundred thousand dalton. The smallestlipopolyssaccharides have a molecular weight of 6,000-8,000 dalton. Onthe other hand, supplemental chemicals and additives are lightermolecules, such as 1,000 dalton, so that they may pass through thissemipermeable membrane of the second filter 11.

[0083] Due to the reduced pressure in the outside of the first filter 10by suction pump 12, dialysate in the first filter 10 is suctioned out.The supplement solution in the second filter is pressed by feeding pump13 to feed in through the second filter 11. The filtration in bothfilters is accelerated by these pumps 12 and 13.

[0084]FIG. 1(a) illustrates an enlargement of the structure of theprimary filter 10 and the secondary filter 11, and the flow of thedialysate and the supplemental solution. As shown in FIG. 1(a), theprimary filter 10 and the secondary filter 11 each comprise a number ofhollow fibers. The sections labeled as Section A are inside the hollowfibers which lead the dialysate rightward to the secondary filter 11.The sections labeled as Section B are outside of the primary filter 10and lead the suctioned filtrate upward to be discarded by the suctionpump 12. The individual sections of Section B appear to be isolated, butin fact, they are in a continuous space leading to the suction pump 12.In the suctioned filtrate, middle molecules of less than 30,000 daltonare thereby removed as indicated by the upward arrow from primary filter10 to the suction pump 12.

[0085] The supplemental solution is stored in a supplemental solutionvessel 14, and it is sent to the second filter by feeding pump 13 asindicated by the downward arrow from the supplemental solution vessel 14and the supplemental liquor line (sections labeled as section C of thesecondary filter 11) into the secondary filter line (sections D on theinside of the hollow fibers of the secondary filter 11). Amino acids,fatty acids, glucose, peptides or any mixture thereof are added into thesupplemental solution through a line which is connected with a valve 24that is equipped in the supplemental solution vessel 14.

[0086] The above-mentioned supplemental solution may be: p1 (a) acommercially available infusion solution or peritoneal dialysate whichis sterilized and packed in a supplemental solution vessel 14, or

[0087] (b) a hemodialysis concentrate or dry chemicals for hemodialysis,which is diluted or dissolved with, reverse osmosis water.

[0088] After partial filtration in the first filter 10 andsupplementation at the second filter 11, the dialysate is flown by pump16 through a warmer 18, where it is warmed up to a standard corporealtemperature. Then, the dialysate is infused through inflow joint 19,bacteria-free filter 20, and joint 21 so as to pass into peritonealcavity 1.

[0089] On the by-pass line 15-17 a-9, a container 17 a is set up, wherea portion of polymer components, which is stored in the peritonealcavity during the daytime, may be stored. The solution can be circulatedthrough the line by pump 15 so as to repeat the concentration/dilutionprocedures. A cooling or freezing unit may be equipped for the container17 a.

[0090] One of the present invention's aims is the reuse of recoveredplasma protein permeated from a patient's body through peritoneum intothe dialysate.

[0091] However, in the case where the recovered protein is not enough toachieve sufficient ultrafiltration, other osmotic agents may besupplemented. Such supplemental agents may be high or low molecularweight substances.

[0092] High molecular weight substances may be oligosaccharides, and lowmolecular weight substances may be glucose or amino acids. Even whensubstances whose daily dose is restricted are used, usage is within atolerable quantity, and those osmotic agents may be used so that therequired osmotic pressure can be obtained. Low molecular weight agentsare added from a supplemental reservoir 14, and high molecular weightagents are supplied from an osmotic agent reservoir 17 b into thecontainer 17 a, where the additives are mixed with the dialysate.

[0093] The recirculation instrument is connected with peritonealcatheters at night so as to automatically achieve peritoneal dialysaterecirculation. However, in the daytime, joint 5 and joint 19 aredisconnected from the recirculation instrument and form a daytimecircuit as illustrated in FIG. 3. For such a disconnection andconnection operation, each joint comprises a respective part a and partb as illustrated in FIG. 2. That is, joint 5 consists of parts 5 a(male) and 5 b (female), and joint 19 consists of parts 19 a (female)and 19 b (male). When parts 5 a and 5 b are disconnected from each otherand parts 19 a and 19 b are disconnected from each other, parts 5 a and19 a can be connected and parts 5 b and 19 b can be connected asillustrated in FIG. 3. According to the present invention, outflow joint5 and inflow joint 19 are set up adjacently in an isolated case 26 andmanipulated from outside of the case to be isolated and free from humancontact.

[0094] By use of the recirculation instrument according to the presentinvention, extraperitoneal recirculation procedures may be achievedcontinuously and automatically in the following way. First, before thepatient begins sleeping, parts 5 a and 19 a and parts 5 b and 19 b,which have been respectively connected in the isolated case 26 duringthe daytime, are disconnected. Then, each part is rotated by 90 degreesto the direction along the arrows as illustrated in FIG. 2. Then, parts5 a and 5 b are connected, and parts 19 a and 19 b are connected to forma recirculating circuit as illustrated in FIG. 1.

[0095] When the circuit line is set up, recirculation is started. Afterconcentrating the drained dialysate and removing uremic toxin in thefirst filter, a portion of the concentrate is stored in the container 17a.

[0096] The remaining concentrate is added to a fresh electrolytesolution through the second filter 11, and then is infused into theperitoneal cavity. If needed, concentrating/diluting procedures arerepeated a few times through a circulation circuit (16-17 a-9). In somecases, an electrolyte solution, such as amino acids, glucose, fattyacids, or peptides, etc., is added.

[0097] Not only sodium caprilate and N-acetyltryptophan are added asstabilizers to prevent the recycled protein from becoming denatured, butacids, alkali, and anti-oxidants, such as, glutathione, vitamin C,vitamin E and reductants, are also added to the electrolyte solution soas to release urea, bilirubin, and S—S bonded chemicals that areattached to cysteine, 34^(th) amino acid from N-terminal of albumin. Bymaking albumin as active as those of healthy persons by theabovementioned way before infusing it into the peritoneal cavity, it maythereby improve the therapy effect.

[0098] Thus, the dialysate in the peritoneal cavity is consistentlydrained out, and is substituted partly with a fresh electrolyte solutionby the way of recirculation at night when the patient sleeps.

[0099] Before getting up in the morning, all or almost all of thedialysate in the peritoneal cavity is drained out, and the drain isrepeatedly concentrated and diluted. Then, the aforementioned chemicalsare added and infused into the peritoneal cavity. The joints 5 and 19are disconnected to form a circuit as illustrated in FIG. 3 by directlyconnecting the corresponding part of joint 5 with the corresponding partof joint 19. Briefly, as in FIG. 3, on the catheter side, an “O” shapedcircuit is formed. On the catheter side, part 19 a is connected to abacteria-free filter entrance 20 on the inflow line, and part 5 a isconnected to an anti-reverse flow-valve exit 4 on the outflow line. Onthe recirculation instrument side, the counter parts 5 b and 19 b areconnected.

[0100] The above-mentioned operation can be manipulated in a separatecase so as to prevent human contact, and through which a continuousrecirculation of the dialysate can be performed.

[0101] By use of the instrument according to the present invention,continuous recirculation can be achieved simultaneous to a partialsubstitution of the dialysate.

[0102] By the instrument according to the present invention, safelyreusing the permeated out protein into the peritoneal dialysate, andcontinuous recirculation of the dialysate can be achieved in thesimplest way. Briefly, every day, dialysate is drained out and infusedthrough a semipermeable membrane, and solution flows through acompletely closed circuit line so as to minimize the risk of infection.

[0103] By the instrument according to the present invention, continuousrecirculation of the dialysate can be achieved simultaneous to a partialsubstitution. As a result, continuous draining of the dialysate out ofthe peritoneal cavity and partial substitution of the dialysate withfresh electrolyte solution can be achieved during the nighttime when thepatient sleeps. After getting up in the morning, the patient can bedisconnected from the instrument and thereafter enjoy a daily life inthe daytime without being connected to an external instrument.

[0104] It has been said that increasing the number of dialysis cyclesper day is effective for improving the dialysance of peritonealdialysis. However, too many cycles of peritoneal dialysis increases thevacancy time of a peritoneal cavity. To solve this problem, the use oftidal type recirculation has been proposed. However, tidal typerecirculation leaves a portion of liquid in the peritoneal cavity, andit can not improve the dialysance significantly.

[0105] The present invention, in contrast, can improve the dialysance,as the dialysate recirculates without a vacancy time in the peritonealcavity. Another recirculating method in which the dialysate is refinedby extraperitoneal dialysis by use of an artificial dialyser andextracoporial dialysate can improve the dialysance, but thisrecirculating method requires a large volume of dialysate. The presentinvention provides a much more economical dialysis due to a partialsubstitution of recirculated dialysate. This advantage is also valid inthe case where no polymer component is contained and recycled.

[0106] Instead of requiring large volumes of dialysate to be delivered,on site preparation of dialysate by diluting the dialysate concentrateor by dissolving dry chemicals is very effective for reducing the costof therapy. The water preparation device for the dissolution anddilution by reverse osmosis membrane may be equipped in the instrumentaccording to the present invention so as to provide a safe and low costdialysate.

[0107] Infection can be prevented by the use of a previously connected,packed and sterilized extracorporeal recirculation line. Also, theinfection rate at a periodical exchange can be significantly reduced byhaving the outflow and inflow connection parts fixed adjacent to oneanother in a closed case as illustrated in FIG. 2, and the connectionparts can be disconnected and exchanged by outside manipulation freefrom contact of the atmosphere and other foreign, e.g. human, contact.

[0108] By using the above-described method and instrument, the presentinvention enables (I) minimizing contact with the atmosphere and otherforeign matters such as human contact, (II) minimizing the plugging ofthe semi-permeable membrane on the recirculation line, and (III)perfectly preventing the invasion of bacterial and endotoxin fromexternal sources.

What is claimed is:
 1. A recirculation method of dialysate whichcomprises continuous flow of dialysate out of peritoneal cavity,recirculation through a closed line, filtering out of a portion of thedialysate through a semipermeable membrane on the way, supplementing acomparable volume of fresh dialysate through a semipermeable membranehaving a maximum permeable molecule of up to 5,000 dalton, and returninginto peritoneal cavity.
 2. The recirculation method of dialysateaccording to claim 1, wherein polymer osmotic agents is added to therecirculation line.
 3. The recirculation method of dialysate accordingto claim 2 wherein polymer osmotic agents is plasma protein oroligosaccharide.
 4. The recirculation method of dialysate according toclaim 1, wherein osmotic agents selected from glucose, amino acids,fatty acids, and peptides is added to the recirculation line.
 5. Therecirculation method of dialysate according to claim 1, whereinreductants or anti-oxidants are added to supplementing fluid.
 6. Therecirculation method of dialysate according to claim 5, whereinreductants or anti-oxidants is glutathione, vitamin C or vitamin E. 7.The recirculation method of dialysate according to claim 1, whereinstabilizers preventing the recycled protein denatured is added tosupplementing fluid.
 8. The recirculation method of dialysate accordingto claim 1, wherein albumin is treated with reductants or anti-oxidantsto activate before infusing into peritoneal cavity.